Cerebrospinal fluid shunt having long term anti-occlusion agent delivery

ABSTRACT

The invention includes a shunt for at least partial implantation into a patient that includes an elongated conduit having at least one lumen therethrough, that includes a proximal end for receipt of bodily fluids for flow through the shunt and a distal end for discharge of the bodily fluids from the shunt, and a long term source of at least one occlusion resistant agent, wherein said at least a portion of the at least one occlusion resistant agent can permeate through at least a portion of the elongated conduit. The invention also includes kits and systems.

RELATED APPLICATIONS

This application is a division of U.S. patent application Ser. No.12/607,419, filed Oct. 28, 2009, which claims priority to U.S. patentapplication Ser. No. 11/380,157, filed Apr. 25, 2006, all of which areincorporated by reference herein.

FIELD OF THE INVENTION

This invention relates to shunts and techniques to prevent blockage orocclusion of such a shunt. One embodiment of the invention relates to acerebrospinal fluid shunt.

BACKGROUND OF THE INVENTION

Hydrocephalic shunts are designed to remove excess fluid from theventricular region of the brain to a different internal location, suchas the peritoneal cavity. Alternatively, cerebral spinal fluid (CSF)shunts may have a proximal end placed into the patient's ventricularregion and a distal end being connected external of the patient. Ineither configuration, a common problem involves the immune responseand/or an inflammatory response of the patient or inflammatory responseto the insertion of the foreign body, i.e., the catheter, therein.Additionally, occlusion of the catheter lumens often occur and precludeeffective drainage of the CSF fluid. It is estimated that 40% ofimplanted hydrocephalic shunts fail within 5 years due to tissueproliferation into the shunt lumen.

U.S. Pat. No. 6,110,155, issued to Baudino, and commonly owned byApplicant of the present application, shows an anti-inflammatory agentloaded catheter distal tip and method for preventing tissue fibrosis.The device and method utilizes, in one embodiment, dexamethasone sodiumphosphate agent on a ventricular catheter tip to prevent encapsulationof the catheter. U.S. Pat. No. 6,348,042 B1, issued to Warren, Jr.,discloses a bio-active shunt device and method by which the interiorlumen surface of a shunt is coated with a matrix forming system havingat least one enzyme configured for inciting activity to preclude thegrowth of obstructing cellular material. In one embodiment, the interiorsurface of the catheter lumen is impregnated with proteases or a matrixcontaining proteases that is impregnated onto the wall of the lumen todegrade cellular material including cells of the choroid plexus andperitoneum.

U.S. Pat. Pub. No. US 2004/0220510, commonly assigned, discloses anocclusion resistant shunt for implantation into a patient to treathydrocephalus. The shunts are constructed to include one or moreocclusion resistant materials. S hunts for the treatment ofhydrocephalus may remain implanted for the lifetime of a patient,therefore there remains a need for an extended duration of localdelivery of agents to limit or prevent occlusion.

BRIEF SUMMARY OF THE INVENTION

An occlusion resistant medical shunt, particularly a hydrocephalicshunt, is provided for implantation into a mammal. The shunt has anelongate wall structure configured as a tube having a lumen therethroughand a proximal end for receipt of bodily fluids. The bodily fluids, suchas cerebrospinal fluid, flows through the shunt to a distal end fordischarge of the bodily fluids. The wall structure of the shuntgenerally includes a biocompatible medical device material. The shuntsof the present invention allow for. long term delivery of one or moreocclusion resistant materials to resist occlusion of the lumenal passageof the shunt.

A fully implanted medical shunt of the invention for use as ahydrocephalus shunting device has a construction which controls theimmunologic response that the recipient may experience after receipt ofthe shunt within the recipient's body, and through the lifetime of theimplantation, which is often the lifetime of the patient. In variousembodiments of the present invention, the shunt comprises an elongatewall structure configured as a tube having a lumen therethrough and aproximal end for receipt of bodily fluids and a distal end for dischargeof said bodily fluids into another portion of the recipient's body. Inone embodiment, the proximal end is located in the ventricular region ofthe brain and the distal end is located in the peritoneal structure atthe abdomen. In another embodiment, the proximal end is located in theventricular region of the brain and the distal end is located externalof the patient. The wall structure generally includes a biocompatibleelastomer material, such as silicone, and a source of one or moreocclusion resistant materials at one or both of the proximal and distalends. In addition to or alternatively, the distal end may have differentmaterial properties than the proximal end in order to optimize theresistance to both occlusion and/or infection.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a schematic view of one example of a shunt catheter inaccordance with the invention.

FIG. 1B is a planar cross section of the portion of the shunt depictedin FIG. 1A that is distal of the A axis.

FIG. 1C is a schematic view of the portion of the shunt depicted in FIG.1A that is distal of the A axis.

FIG. 2A is a planar cross section of another example of a shunt catheterin accordance with the invention.

FIG. 2B is a cross section of the portion of the shunt depicted in FIG.2A that is distal of the B axis.

DETAILED DESCRIPTION OF THE INVENTION

A shunt in accordance with the invention can be used in any medicalapplication where it is necessary to move fluid from one part of thebody to another. Examples of types of shunts where the invention can beutilized include, but are not limited to, cardiac shunts, cerebralshunts, glaucoma shunts, urinary catheters, and drainage catheters fortrauma or post-surgical applications.

Shunts for treatment of hydrocephalus are well known and have evolvedover many decades. Typically, a hydrocephalic shunt includes tubing witha proximal end located in the brain tissue and a distal end locatedeither within the patient at another location external to the brain orexternal of the patient altogether. Such shunts also typically include avalve structure designed to accommodate and/or control flow based on theintracranial pressure and the position of the patient or other factors.One example includes a valve that is configured for proper flowregulation when the patient is laying down versus standing up.

A shunt may be occluded at three different locations. First, at an entrypoint such as the proximal location in the brain, second, at or near thevalve system, commonly referred to as a “valve obstruction”, and third,at the distal end, referred to as a distal catheter occlusion. Shunts inaccordance with one embodiment of this invention focus on either distalor proximal occlusions rather than valve obstructions, although valveobstructions may be a sequel of occlusions or infection migrating fromthe distal or proximal ends.

Proximal occlusions are generally more common than distal occlusions,and often result from blood or cellular debris which block the lumen anddistal holes on ventricular catheters. This growth may depend onartificial properties (chemistry and geometry) as well as the distancebetween catheter and tissues in the ventricular (catheter positioningand slit ventricles syndrome). Some ventricular catheter tip designshave been proposed for maintaining the holes of the ventricular catheteraway from the walls of the ventricles and the choroids plexus in orderto resolve this problem. However, such devices are likely unable tofully prevent proximal occlusion from occurring or may present furtherproblems. Moreover, those known as flanged catheters actually promotefirm attachment of the catheter tubing to the choroids plexus. Althoughdistal obstructions are not as frequent as that at the proximal end,shunt-type catheters can be obstructed in the peritoneal cavity byingrowth of mesothelial cells and fibroblasts.

Shunts of the invention provide long term delivery of one or moreocclusion resistant agents. The long term delivery of the one or moreocclusion resistant agents is provided through a long term source of theone or more occlusion resistant agents. As used herein, the phrase longterm source means that the shunt can deliver at least one occlusionresistant agent for at least 1 year. In another embodiment, the phraselong term source means that the shunt can deliver at least one occlusionresistant agent for at least 5 years. In yet another embodiment, thephrase long term source means that the shunt can deliver at least oneocclusion resistant agent for at least 10 years. In a furtherembodiment, the term long term source means that the shunt can deliverat least one occlusion resistant agent for the entire period in whichthe shunt is implanted in the patient, or the lifetime of the patient.The long term source of the occlusion resistant agent can be provided byhaving a refilling port in the shunt, or can be provided from within theshunt itself.

The at least one occlusion resistant agent can be delivered at a level,rate, or concentration that is effective to decrease, diminish, orprevent occlusion. The particular concentration that the occlusionresistant agent is effective at will depend at least in part on theidentity of the occlusion resistant agent. Many occlusion resistantagents are effective at a concentration between about 1 nanomolar (nM)and about 1 millimoloar (mM). In one embodiment, where the at least oneocclusion resistant agent is rapamycin, the concentration whererapamycin is effective is at a concentration of about 1 nM or higher.

FIG. 1 shows one embodiment of the hydrocephalic or CSF shunt 10 of thepresent invention, wherein the shunt 10 includes an elongated conduit 11having a proximal portion 12, one or more ports 13, one or more valves14, a central portion 15, and a distal portion 16. The elongated conduit11 may be of any shape or size, but generally will be in the form of atube made of an elastomeric material. As noted above, proximal portion12 is placed in the patient's head at the region of the ventricles whilethe central portion 15 is routed subcutaneously along the patient's neckand torso. The distal portion 16 may be placed for drainage of thecerebral spinal fluid into the peritoneal cavity where the fluid is thenreabsorbed by the normal bodily processes or may extend out of thepatients body for external drainage. In yet another embodiment, thedistal portion 16 of a shunt 20 in accordance with the invention isconnected to a distal catheter that drains cerebral spinal fluid (forexample) into another portion of the body.

The elongated conduit 11 can be fabricated from a number of materials,as is known to one of skill in the art having read this specification.Examples of such materials include, but are not limited to poly(L-lacticacid), poly(lactide-co-glycolide), poly(hydroxybutyrate-co-valerate),silicones, polyurethanes, polyesters, vinyl homopolymers and copolymers,acrylate homopolymers and copolymers, polyethers, polyethylene,polypropylene, polycarbonate, polysulfone, cellulosics,polydimethylsiloxanes, methylhydrosiloxane-dimethylsiloxane copolymers,polymethylhydrosiloxanes, polyethylhydrosiloxanes, hydride terminatedpolyphenyl (dimethylhydrosiloxy)siloxanes,methylhydrosiloxane-phenylmethylsiloxane copolymers,N,-vinylpyrrolidone/methylm ethacrylate copolymers,2-hydroxyethylacrylate (e.g. polymacon), various copolymers of2-hydroxyethylmethacrylate (e.g, hafilcon A and B, vifilcon A,tetrafilcon, dimefilcon, bufilcon, perfilcon, etc.), copolymers ofN-vinylpyrrolidone (e.g. lidofilcon A and B, scafilcon A, surfilcon,vifilcon, filcon YA, etc.), polyamides, polyimides, fluoropolymers,polytetrafluoroethylenes, natural rubber and polyisoprene.

In the embodiment depicted in FIG. 1A, the port 13 can provide long termdelivery of one or more occlusion resistant agents or materials toresist occlusion of the lumenal passage of the shunt. The at least oneport 13 can be constructed as would be known to those of skill in theart having read this specification.

In one embodiment, the port 13 can include a conventional percutaneousfill port that includes a membrane that can be penetrated by ahypodermic needle and is self-sealing after the needle is removed. Inone embodiment, the fluid that is injected from the needle goes througha structure that functions as a funnel to a reservoir The fluid, whichgenerally comprises one or more occlusion resistant agents, flows fromthe reservoir to the one or more portions of the shunt where occlusionis to be minimized. In one embodiment, a percutaneous fill port alsoincludes a valve to control the rate at which the fluid travels from thereservoir to the one or more portions of the shunt where occlusion is tobe minimized. An example of a percutaneous fill port that could functionas port 13 can be found in U.S. Pat. No. 5,697,951, the disclosure ofwhich is incorporated by reference herein. Other examples of types ofstructure that could be utilized as a port 13 include, but are notlimited to the center reservoir fill ports of the MEDTRONIC SYNCHROMED®Infusion System and the MEDTRONIC ISOMED® Constant-Flow Infusion System.

The valve 14 can be, but need not be part of the shunt 20 of theinvention. In one embodiment, the valve 14 is a separate component thatis configured to be connected to and work with a shunt 20 of theinvention. One of skill in the art, having read this specification, willunderstand the particular types of valves that may be utilized. Inembodiments of the invention that are to be used for drainage ofcerebral spinal fluid from the brain to another portion of the body,commercially available valves, including, but not limited to, PS MedicalStrata® valve, and PS Medical Delta® valve can be utilized.

In one embodiment, depicted in FIGS. 1B and 1C, the proximal end 12 isat least one of the areas where occlusion is to be minimized. Oneembodiment of a shunt 10 includes apertures 17 that allow the receipt ofbodily fluids, such as CSF into the shunt 10. The wall 18 is generallymade of an absorptive material. As used herein, the term “absorptivematerial” refers to a material that can absorb some amount of at leastone occlusion resistant agent. The wall 18 can be constructed of onetype of absorptive material, more than one type of absorptive material,or one or more types of absorptive material and one or more othermaterials. For example, at least the proximal portion 12 can beconstructed of one type of absorptive material and can have apertures 17formed therein. In another embodiment, at least the proximal portion 12can be constructed of materials that are commonly known to those ofskill in the art for shunt construction, and the absorptive material canbe added to the proximal portion. In such an embodiment, the absorptivematerial could be attached to the commonly used shunt materials.Examples of methods of attachment include, but are not limited to,solvent boding, thermal bonding, adhesives, and other methods known tothose of skill in the art having read this specification.

In one embodiment, absorptive materials can include any material thatcan absorb at least some of at least one occlusion resistant agent. Inone embodiment, an absorptive material can include a material that hasan affinity for the occlusion resistant agent due at least in part bythe fact that it is delivered in solution. In another embodiment,absorptive materials can have a selective affinity for at least oneocclusion resistant agent. Selective affinities can include grosschemical properties, such as hydrophobic attraction, hydrophilicattraction, or ionic attraction; or more specific affinities such asimmuno-based affinity, and molecular imprinting based affinity. Otherembodiments can include absorptive materials that have affinities basedon gross chemical properties, specific affinities, or any combinationthereof. Examples of types of absorptive materials include, but are notlimited to, alumina, silica, activated charcoal, cross-linkedpolystyrene beads, high molecular weight gels such as polyethyleneglycol (PEG), silicone polyurethanes, and open-celled foams. Oneparticular example of an open-celled foam that may be useful inembodiments of the invention is a hydrophilic medical grade foamavailable from Avitar Technologies (Canton, Mass.). These exemplarymaterials or materials like them could then be modified to provide oneor more selective affinities as discussed above. One of skill in theart, having read this specification, would understand and be able tomodify such materials in order to alter the affinities thereof in afashion to make them more or less selective for one or more occlusionresistant agents.

A cross section of another embodiment of the invention that can providelong term delivery of one or more occlusion resistant agents is depictedin FIG. 2A. In this embodiment, the elongated conduit 11 of the shunt 20includes at least two lumens, the fluid conduit 21 and the drainageconduit 22. The drainage conduit 22 is also referred to herein as theCSF drainage conduit 22, because in some embodiments it serves as theconduit for the CSF from the apertures 17 of the proximal portion 12through the central portion 15 (not shown) to the distal portion (alsonot shown) where it drains either into another body space of the patientor external to the patient. The fluid conduit 21 is in fluidcommunication with the port 13. The fluid that is injected into the port13 can travel from the port 13 into the fluid conduit 21. The fluid,containing the occlusion resistant agent can then permeate through thesurface of the fluid conduit 21 so that the occlusion resistant agent isdelivered to the space around the shunt 20 in the ventricular space, thevolumes within the apertures 17, and the volume within the CSF conduit22 in at least the proximal portion 12 of the CSF shunt 20. Although notnecessarily depicted in FIG. 2A, the fluid conduit 21 can be used tocommunicate between the port 13 and the proximal portion 12 of the shunt20. The fluid conduit 21 can therefore allow for fluid communicationthroughout the length of the shunt 20.

In such an embodiment therefore, the material that forms the fluidconduit 2 1 is at least somewhat permeable the one or more occlusionresistant agent. Examples of material that can be used to construct thefluid conduit 21 include, but are not limited to silicone rubber, andpolyurethane. In one embodiment, the fluid conduit 21 is made ofsilicone rubber.

The fluid conduit 21 can have variable properties across its length. Forexample, it may be advantageous to have thicker walls at some pointsalong the fluid conduit 21 in order to provide structural integrity toparticular portions of the proximal portion 12 of the shunt 12 or toslow the passage of the occlusion resistant agent across some portionsof the fluid conduit 21. It may also be advantageous to have thinnerwalls at some points along the fluid conduit 21 in order to increase therate and/or the amount of occlusion resistant agent that is delivered tothe space around some portions of shunt 20. Therefore, in one embodimentof the invention, the thickness of the wall of the fluid conduit 21 canvary over its length. The particular thicknesses, and locations ofdifferent thicknesses can be chosen based on a number of factors,including but not limited to, the structural integrity of the shunt 20,a desire to slow passage or decrease the amount of the one or moreocclusion resistant agent to some portions of the area around or withinthe shunt 20, a desire to speed passage or increase the amount of theone or more occlusion resistant agent to some portions of the areaaround or within the shunt 20, or some combination thereof.

One exemplary embodiment of the invention includes a shunt 20 with avariable wall thickness fluid conduit 21. One example includes a fluidconduit 21 that has a wall that is thinner on the outer surface of theshunt 20 than it is on the inner surface (the surface facing the CSFconduit 22) of the shunt 20. It should also be noted that otherproperties of the material making up the fluid conduit 21 wall could bemodified in order to change the rate and/or amount of occlusionresistant agent that permeates the fluid conduit 21.

FIG. 2B illustrates how a shunt in accordance with this embodiment ofthe invention could function to both drain CSF from the ventricles andrelease occlusion resistant agent. In this depiction, the CSF flow isrepresented by the thin arrows, of which some are designated 23. The CSFflows from the space around the shunt 20 through the apertures 17 andinto the CSF conduit 22. The flow of the occlusion resistant agent isrepresented by the thick arrows, of which some are designated 25. Theocclusion resistant agent permeates the walls of the fluid conduit 21and flows into the space around the shunt 20 (exemplified by arrow 25a), the space within the CSF conduit 22 (exemplified by arrow 25 b), andinto the volume within the apertures 17 (exemplified by arrow 25 c). Itshould be noted that any one or more of the directions of flow of theocclusion resistant agent could be controlled or modified at least inpart by changing the thickness of the wall through which that particularflow occurs. For example, to configure a shunt that preferentially flowsocclusion resistant agent to the space around the shunt 20 as opposed toflowing occlusion resistant agent to the area within the CSF conduit 22,the outside walls of the fluid conduit 21 could be made thinner than theinside walls (those facing the CSF conduit 22). Such an embodiment mayfunction to minimize the flow depicted by arrow 25 b. Other resultscould also be obtained by varying the wall thicknesses of differentareas of the fluid conduit 21.

Another possible embodiment that is similar to that depicted in FIG. 2Bis to have a spiral configuration to the apertures in the fluid conduit21. Such a configuration may provide a compromise between total aperturevolume and structural integrity that may be advantageous or desirable.

Another embodiment of the invention includes a shunt 20 that includes aCSF conduit 22, a fluid conduit 21, and absorptive material within thefluid conduit 21. In such an embodiment, the absorptive material can beincluded in the entire fluid conduit 21, or some portion thereof. In oneembodiment, the absorptive material is included in a proximal portion ofthe fluid conduit 21. In such an embodiment, the fluid that is injectedinto the fluid conduit 21 via the port 13 would reach the absorptivematerial via the fluid conduit 21 and the occlusion resistant agentcould be absorbed at least in part by the absorptive material.

Another embodiment of the invention includes a shunt 20 that includes aCSF conduit 22, a fluid conduit 2 1, and a saturated solution containingone or more occlusion resistant agents. In one embodiment, the saturatedsolution includes at least one carrier fluid, and at least one occlusionresistant agent in solid form. In one embodiment, the at least oneocclusion resistant agent is at a concentration that is higher than it'ssolubility in the carrier liquid. In one embodiment, the carrier fluidis water, saline, buffered saline. In one embodiment, the at least oneocclusion resistant agent is a hydrophobic compound with a relativelylow water solubility. In one embodiment the at least one occlusionresistant agent is a hydrophobic compound with a water solubility ofless than about 1 milligram/milliliter (mg/mL).

In an embodiment that includes a saturated solution containing one ormore occlusion resistant agents with the occlusion resistant agent at aconcentration that is higher than it's solubility, an equilibrium willbe maintained between the occlusion resistant agent in the saturatedsolution in the fluid conduit 21 and outside wall of the fluid conduit21. This equilibrium allows the saturated solution itself to act as along term source of the at least one occlusion resistant agent. Theequilibrium of the occlusion resistant agent and diffusion of theocclusion resistant agent through the wall of the fluid conduit 21 willallow the shunt 20 to deliver an almost constant concentration of theocclusion resistant agent into the area around and within the shunt 20.

Because a large quantity of the occlusion resistant agent can be storedin the fluid conduit 21 by using a saturated solution, the saturatedsolution can be it's own long term source for the occlusion resistantagent, and therefore a shunt 20 that utilizes a saturated solution doesnot necessarily have to include a port 13.

The inclusion of an occlusion resistant agent in a shunt 20 can beutilized in any region of the shunt. One of skill in the art, havingread this specification, would understand how to, for example, utilize afluid conduit portion in a region other than the proximal portion 12 ofthe shunt 20. Other regions that could be configured to deliverocclusion resistant agents on a long term basis include the proximalportion 12, the distal portion 18, valve portion 14, or any combinationthereof. Generally, the occlusion resistant agent is delivered throughportions of the shunt where clotting or tissue growth tend to occludethe lumen of the shunt.

Occlusion resistant agents can include a number of different types ofagents that can be selected from multiple classes. Such classes includeanti-inflammatory drugs, immuno-suppressive drugs, anti-cancer drugs,anti-proliferatives, anti-migratories, anti-angiogenic drugs,radioactive or radiation-emitting material. Such classes may furtherinclude anti-neoplastics, anti-coagulents, anti-thrombogenics,anti-oxidants, cyclooxygenase inhibitors, calcium entry blockers,anti-neoplastics, anti-mitotics, anti-microbials, ait; ic oxide donors,cell cycle inhibitors, znti-arthritis agents, ad-diaibetic agents,thrombin inhibitors, thrombolytics, antibiotics, antiviral agents,antiproliferatives, anti-thrombogenics, anti-oxidants, cyclooxygenaseinhibitors, calcium entry blockers, antbmitotics, anti-microbials,nitric oxide donors, cell cycle inhibitors, anti-cancer agents, and genetherapy agents.

The following classes of anti-occlusion agents with examples in eachclass are exemplary occlusion resistant agents that can be utilized inthe invention. For example classes of anti-occlusion agents that may beutilized in embodiments of the invention include immunosuppressives,anti-inflammatories, anti-neoplastics, anti-angiogenics,anti-coagulants, analgesics, antipyretics, anti-proliferatives,anti-thrombogenics, anti-oxidants, cyclooxygenase inhibitors, calciumentry blockers, anti-neoplastics, antimitotics, anti-microbials,antihgals, nitric oxide donors, cell cycle inhibitors, anticanceragents, anti-arthritis agents, anti-diabetic agents, thrombininhibitors, thrombolytics, antibiotics, antiviral agents, and genetherapy agents. The following list provides additional examples ofocclusion resistant agents that may be utilized in the invention.

Anti-inflammatory agents that may be utilized in the invention include,but are not limited to selective NF-kappaB modulators, NF-kappaBmodulators (non-specific), steroids, infallmatory cytokine inhibitors,P38 inhibitorslstress kinase inhibitors, IL-1 specific inhibitors, TNFspecific inhibitors, adhesion inhibitors, chemokines and their receptorinhibitors, MMP inhibitors or other protease inhibitors, NO modulators,non-steroidal anti,-inflammatory drugs (NSAIDs), and COX inhibitors.

Non-steroidal anti-inflammatory agents including their racemic mixturesor individual enantiomers where applicable—ibuprofen, flurbiprofen,ketoprofen, aclofenac, diclofenac, aloxiprin, aproxen, aspirin,diflunisal, fenoprofen, indomethacin, mefenamic acid, naproxen,phenylbutazone, piroxicam, salicylamide, salicylic acid, sulindac,desoxysulindac, tenoxicam, tramadol, ketoralac, flufenisal, salsalate,triethanolamine salicylate, aminopyrine, antipyrine, oxyphenbutazone,apazone, cintazone, flufenamic acid, clonixerl, clonixin, meclofenamicacid, flunixin, coichicine, demecolcine, allopurinol, oxypurinol,benzydamine hydrochloride, dimefadane, indoxole, intrazole, mimbanehydrochloride, paranylene hydrochloride, tetrydamine, benzindopyrinehydrochloride, fluprofen, ibufenac, naproxol, fenbufen, cinchophen,diflumidone sodium, fenamole, flutiazin, metazamide, letimidehydrochloride, nexeridine hydrochloride, octazamide, molinazole,neocinchophen, nimazole, proxazole citrate, tesicam, tesimide, tolmetin,triflumidate, nepafenac, etodolac, rebamipide, and zaltoprofen.

Other types of not previously categorized anti-inflammatory agents mayalso be utilized in the invention, examples include, but are not limitedto tranilast, rituximab, piroxicam, loxoprofen, doxycyclin, drotrecoginalfa, and tretinoin.

Antineoplastic/antiangiogenic-, -antimetabolite agents, alkylatingagents, cytotoxic antibiotics, vinca alkaloids, mitosis inhibitors,platinum compounds, tissue growth factor inhibitors, cisplatin andetoposide

Immunosuppressant agents—cyclosporine A, mycophenolic acid, tacrolimus,rapamycin, rapamycin analogues, such as rapamycin ABT-578 analogueproduced by Abbott Laboratories, azathioprine, recombinant or monoclonalantibodies to interleukins, T-cells, B-cells and/or their receptors.

Antithrombogenic Factors—Anticoagulents, such as heparin and chondroitensulfate; Platelet inhibitors such as ticlopidine; Vasodilators such ascyclandelate, isoxsuprine, papaverine, dipyrimadole, isosorbidedinitrate, phentolamine, nicotinyl alcohol, co-dergocrine, nicotinicacid, glycerl trinitrate, pentaerythritol tetranitrate and xanthinol;and Thrombolytic agents, such as stretokinase, urokinase and tissueplasminogin activators.

Antiproliferative agents—paclitaxel, actinomycin D, rapamycin,tacrolimus, everolimus, dexamethasone and rapamycin analogue (ABT-578)produced by Abbott Laboratories;

Analgesics and antipyretics—the opioid analgesics such as buprenorphine,dextromoramide, dextropropoxyphene, fentanyl, alfentanil, sufentanil,hydromorphone, methadone, morphine, oxycodone, papaveretum, pentazocine,pethidine, phenopefidine, codeine dihydrocodeine; acetylsalicylic acid(aspirin), paracetamol, and phenazone;

Antimicrobials—the cephalosporins such as cephalexin, cefoxytin andcephalothin;

Antifungals—amorolfine, isoconazole, clotrimazole, econazole,miconazole, nystatin, terbinafine, bifonazole, amphotericin, griseofulvin, ketoconazole, fluconazole and flucytosine, salicylic acid,fezatione, ticlatone, tolnaflate, triacetin, zinc, pyrithione and sodiumpyrithione;

Antiviral agents—acyclovir and acyclovir prodrugs, famcyclovir,zidovudine, didanosine, stavudine, larnivudine, zalcitabine, saquinavir,indinavir, ritonavir, n-docosanol, tromantadine and idoxuridine;

Local anaesthetics—benzocaine, bupivacaine, amethocaine, lignocaine,lidocaine, cocaine, cinchocaine, dibucaine, mepivacaine, prilocalne,etidocaine, veratridine (specific c-fiber blocker) and procaine;

Other miscellaneous antibiotics—chloramphenicol, clindamycin,erythromycin, erythromycin ethyl carbonate, erythromycin estolate,erythromycin glucepate, erythromycin ethylsuccinate, erythromycinlactobionate, roxithromycin, lincomycin, natamycin, nitrofurantoin,spectinomycin, vancomycin, aztreonam, colistin IV, metronidazole,tinidazole, fusidic acid, trimethoprim, and 2-thiopyridine N-oxide;halogen compounds, particularly iodine and iodine compounds such asiodine-PVP complex and diiodohydroxyquin, hexachlorophene;chlorhexidine; chloroamine compounds; and benzoyiperoxide;

Other pharmaceutical agents—beta-radiation emitting isotopes,beclomethasone, fluorometholone, tranilast, ketoprofen, curcumin,cyclosporin A, deoxyspergualin, FK506, sulindac, myriocin,2-aminochromone (U-86983), colchicines, pentosan, antisenseoligonucleotides, mycophenolic acid, etoposide, actinomycin D,camptothecin, carmustine, methotrexate, adriamycin, mitomycin,cis-platinum, mitosis inhibitors, vinca alkaloids, tissue growth factorinhibitors, platinum compounds, cytotoxic inhibitors, alkylating agents,antimetabolite agents, tacrolimus, azathioprine, recombinant ormonoclonal antibodies to interleukins, T-cells, B-cells, and receptors,bisantrene, retinoic acid, tamoxifen, compounds containing silver,doxorubicin, azacytidine, homoharringtonine, selenium compounds,superoxide-dismutase, interferons, heparin, analogs, homologs, andderivatives of the above group.

Embodiments of the invention can include one or more of the aboveexemplified occlusion resistant agents. Embodiments of the invention canalso utilize any combination of the above occlusion resistant agents.Embodiments of the invention can also include other agents, includingbut not limited to, stabilizing agents such as anti-oxidants, radiopaqueagents, MRI detectable agents, and ultrasound detectable agents.

An example of the use of one of the occlusion resistant agents isillustrated herein. In an embodiment that includes a saturated solution,one example of an occlusion resistant agent that may be utilizedincludes rapamycin. Rapamycin is an anti-proliferative agent that can beeffective at a concentration of about 1 nM.

Generally, the flow rate of CSF in a young patient (mean 28.7 years old)is 26.6±14.4 ml/hr; and in an elderly patient (mean 77.1 years old) is 11.4 4.±ml/hr. Therefore, the highest likely flow rate would be 26.6+14.4m/hr or about 41 ml/hr. If one of skill in the art wanted a CSF shuntwith a saturated solution to deliver an effective concentration ofrapamycin over the period of 10 years (as an example), the amount ofrapamycin that would have to be loaded in the CSF shunt would be about0.033 g.

${{\frac{914\mspace{14mu} g}{{x--}1\mspace{14mu} {mol}} \times \frac{{10 \times 10} - {9\mspace{14mu} {mol}}}{1\mspace{14mu} L\mspace{14mu} 1\mspace{14mu} {hour}\mspace{14mu} 1\mspace{14mu} {day}\mspace{14mu} 1\mspace{14mu} {year}} \times 0.04\; 1\mspace{14mu} L\mspace{14mu} 24\mspace{14mu} {hours}\mspace{14mu} 365\mspace{14mu} {days}\mspace{14mu} 10\mspace{14mu} {years}} = {32\text{,}827\text{,}224\mspace{14mu} a\mspace{14mu} 0}},{033\mspace{14mu} {g--}},{{xxx}--}$

Another method of calculating the amount of rapamycin that would beneeded for a CSF shunt containing a saturated solution to deliver aneffective concentration over the period of 10 years (an exemplary periodof time) follows:

If the rate of formation of CSF is about 500 mllday, then:365 days 500 ml 10 yrs x-----x−=1,825,000 ml r 1,825 liters of CSFformed in 10 years 1, year dayIf it is assumed that the minimal rapamycin concentration (e.g. ofrapaymcin should be about 1×1 M, then: 10×10-9 moles 914 g9,140˜10˜g-x--.=,-.------.1 liter 1 mole 1 literThen the amount of rapamycin necessary for 10 years is:1,825 liters CSF×9,14O˜1O-˜g=0.01668 grams rapamycin˜0.017 gramsrapamycin 1 liter

If the saturated solution contained 50% solid rapamycin; 10%anti-oxidant stabilizers; 20% radiopacity agents; and 20% fluid (saline,water, etc.), then the volume of saturated solution that would benecessary would be about 0.066 ml (assuming the density of the saturatedsolution was about 1.0 g/mL). One of skill in the art, having read thisspecification, will be able to adjust the concentration of thecomponents to achieve iso-osmotic strength relative to CSF fluid tominimize swelling or shrinkage due to osmotic driven transport of wateracross the device wall.

The invention also includes a system having at least one shunt of theinvention. In one embodiment, a system includes a shunt in accordancewith the invention, having a valve, and a distal catheter. The inventionalso includes kits that include at least one shunt of the invention. Inone embodiment, a kit includes a shunt in accordance with the invention,a valve, and a distal catheter.

One skilled in the art will appreciate that the present invention can bepracticed with embodiments other than those disclosed. The disclosedembodiments are presented for purposes of illustration and notlimitation, and the present invention is limited only by the claims thatfollow.

1-39. (canceled)
 40. A shunt for at least partial implantation into a patient having a brain with a ventricular region and having an abdomen, comprising: an elongated conduit having a first lumen extending therethrough and a second lumen concentric about said first lumen along at least a part of said first lumen, wherein said elongated conduit comprises a proximal end configured for receipt of bodily fluids from said ventricular region of said brain for flow through said shunt and a distal end for discharge of said bodily fluids from said shunt into said abdomen; and a long term source of at least one occlusion resistant agent fluidly coupled to said second lumen, wherein said at least one occlusion resistant agent can permeate through a permeable portion of said second lumen into the first lumen.
 41. The shunt of claim 40, wherein said long term source comprises a refill port that is in fluid communication with said second lumen of said elongated conduit.
 42. The shunt of claim 41, wherein said refill port includes a percutaneous access port.
 43. The shunt of claim 40, wherein said second lumen extends through said elongated conduit.
 44. The shunt of claim 40, wherein said first lumen is a fluid conduit for drainage of cerebrospinal fluid and where said second lumen is a conduit for said at least one occlusion resistant agent.
 45. The shunt of claim 44, wherein said permeable portion is a wall defining, at least in part, said second lumen.
 46. The shunt of claim 44, further comprising a refill port that is in fluid communication with said fluid conduit.
 47. The shunt of claim 46, wherein said refill port includes a percutaneous access port.
 48. The shunt of claim 44, wherein at least a portion of said fluid conduit contains at least one absorptive agent and said at least one occlusion resistant agent.
 49. The shunt of claim 48, wherein said absorptive agent is at least one of alumina, silica, activated charcoal, cross-linked polystyrene beads, high molecular weight gels, silicone polyurethanes and open-celled foams.
 50. The shunt of claim 44, wherein at least a portion of said fluid conduit contains a saturated solution that includes said at least one occlusion resistant agent.
 51. The shunt of claim 50, wherein the at least one occlusion resistant agent has a solubility of less than 1 mg/mL in water.
 52. The shunt of claim 50, wherein the at least one occlusion resistant agent is rapamycin.
 53. The shunt of claim 40, wherein said occlusion-resistant agent comprises an immunosuppressive, an anti-inflammatory, an anti-neoplastic, a radiation emitting material, an anti-angiogenic, an anti-coagulant, an anti-proliferative, an anti-thrombogenic, an anti-oxidant, a cyclooxygenase inhibitor, a calcium entry blocker, an anti-neoplastic, an anti-mitotic, an anti-microbial, a nitric oxide donor, a cell cycle inhibitor, an anti-cancer agent, an anti-arthritis agent, an anti-diabetic agent, a thrombin inhibitor, a thrombolytic, an antibiotic, an antiviral agent, a gene therapy agent, or some combination thereof.
 54. The shunt of claim 45, wherein said wall of said fluid conduit has a first location and a second location, and wherein said occlusion-resistant agent permeates at a first rate at said first location and a second rate different from said first rate at said second location.
 55. The shunt of claim 54, wherein said permeable portion has a first thickness at said first location and a second thickness different from said first thickness at said second location, and wherein said first rate and said second rate is based, at least in part, on said first thickness and said second thickness, respectively.
 56. The shunt of claim 40, further comprising a plurality of apertures extending between the proximal end of the elongated conduit and an exterior of the shunt, the plurality of apertures configured to enable passage of the bodily fluids in to the first lumen without flowing into the second lumen.
 57. The shunt of claim 56, wherein the at least one occlusion resistant agent can further permeate through the permeable portion of the second lumen into the apertures.
 58. The shunt of claim 56, wherein the at least one occlusion resistant agent can further permeate outwardly from the permeable portion of the second lumen into the ventricular region of the brain.
 59. A kit comprising: a shunt for at least partial implantation into a patient having a brain with a ventricular region and having abdomen comprising: an elongated conduit having a first lumen extending therethrough and a second lumen concentric about said first lumen along at least a part of said first lumen, wherein said elongated conduit comprises a proximal end configured for receipt of bodily fluids from said ventricular region of said brain for flow through said shunt and a distal end for discharge of said bodily fluids from said shunt into said abdomen; and a long term source of at least one occlusion resistant agent fluidly coupled to said second lumen, wherein said at least one occlusion resistant agent can permeate through a permeable portion of said second lumen into the first lumen; a valve; and a distal catheter.
 60. The kit of claim 59, wherein said second lumen extends through said elongated conduit.
 61. The kit of claim 59, wherein said first lumen is a fluid conduit for drainage of cerebrospinal fluid, and where said second lumen is a conduit for said at least one occlusion resistant agent.
 62. The kit of claim 59, wherein said permeable portion is a wall defining, at least in part, said second lumen.
 63. The kit of claim 59, further comprising a refill port that is in fluid communication with said fluid conduit.
 64. The kit of claim 63, wherein said refill port includes a percutaneous access port.
 65. The kit of claim 59, wherein at least a portion of said fluid conduit contains at least one absorptive agent and said at least one occlusion resistant agent.
 66. The kit of claim 65, wherein said absorptive agent is at least one of alumina, silica, activated charcoal, cross-linked polystyrene beads, high molecular weight gels, silicone polyurethanes and open-celled foams.
 67. The kit of claim 59, wherein at least a portion of said fluid conduit contains a saturated solution that includes said at least one occlusion resistant agent.
 68. The kit of claim 59, wherein the at least one occlusion resistant agent has a solubility of less than 1 mg/mL in water.
 69. The kit of claim 59, wherein the at least one occlusion resistant agent is rapamycin.
 70. The kit of claim 59, wherein the shunt further comprises a plurality of apertures extending between the proximal end of the elongated conduit and an exterior of the shunt, the plurality of apertures configured to enable passage of the bodily fluids in to the first lumen without flowing into the second lumen.
 71. The kit of claim 70, wherein the at least one occlusion resistant agent can further permeate through the permeable portion of the second lumen into the apertures.
 72. The kit of claim 70, wherein the at least one occlusion resistant agent can further permeate outwardly from the permeable portion of the second lumen into the ventricular region of the brain. 